POS1332 TOWARD SAFER GLUCOCORTICOID THERAPY OF POLYMYALGIA RHEUMATICA
Authors: X. Pan, Q. Hou, J. Xu, Y. MA, J. LI, M. LI, J. Su, X. Shi, W. Bracken, D. Katz
Journal: Annals of the Rheumatic Diseases (2022)

Background SPI-62 is a potent 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitor entering Phase 2 development as adjunctive therapy to prednisolone in polymyalgia rheumatica, as well as for treatment of Cushing’s syndrome and autonomous cortisol secretion. HSD-1, an intracellular enzyme, activates glucocorticoids in target tissues in which glucocorticoid medicines are associated with morbidity including liver, adipose, muscle, and skin. In Phase 1 clinical trials SPI-62 was generally well tolerated and associated with maximal liver and brain HSD-1 inhibition. Objectives To demonstrate mitigation by SPI-62 of corticosterone (CORT) adverse effects in mouse. Methods C57BL/6 male mice (age 7 weeks; n=14 per group) were administered CORT (100 g/mL in drinking water) and SPI-62 (by gavage in 0.5% HPMC; 0, 1, or 10 mg/kg/day or 10 mg/kg twice daily) for 35 days. A control group received no CORT or SPI-62. Body weight was assessed daily and food consumption twice weekly. Whole body muscle and fat amounts were measured at Days 0, 14, and 28 using an EchoMRI-130H body composition analyzer. Blood samples for fasting glucose and insulin were obtained at Days 1 (pre-dose), 15, 29, and 35. An open field test was conducted on Day 22. A grip strength test was performed on Day 28. After sacrifice on Day 36, gonadal, subcutaneous, retroperitoneal, and mesenteric fat, quadriceps, and tibialis anterior were dissected and weighed, and skin was formalin fixed and paraffin embedded. Results One control mouse died due to accidental gavage injury. Two mice who received CORT + 0.5% HPMC died on Days 11 and 19. CORT resulted in increased food consumption which was normalized by SPI-62 in a dose-dependent manner. CORT-treated mice showed reduced body weight gain for 2 weeks then accelerated body weight gain. SPI-62 prevented body weight gain acceleration in a dose-dependent manner. CORT effects on dermal thickness and structure were less prominent in mice who also received SPI-62. No effect of CORT or SPI-62 was observed in the open field test. SPI-62 prevented CORT adverse effects of insulin resistance, increased adiposity, skeletal myoatrophy, and grip strength reduction (Table 1). Table 1. Observed percentage difference of treatment group mean, compared to control group mean, in CORT-treated mice SPI-62 treatment none 1 mg/kg1x/day 10 mg/kg1x/day 10 mg/kg2x/day HOMA-IR Day 15 +422 +428 +104 +8 HOMA-IR Day 29 +788 +472 +204 +14 HOMA-IR Day 35 +3620 +1270 +324 +92 Body fat content Day 14* +110 +72 -13 -7 Body fat content Day 28* +166 +102 +63 -12 Gonadal fat weight* +151 +74 +39 -1 Subcutaneous fat weight* +471 +121 +83 +7 Retroperitoneal fat weight* +227 +89 +36 +25 Mesenteric fat weight* +240 +133 +124 +71 Body muscle content Day 14* -10 -7 0 +1 Body muscle content Day 28* -15 -8 -6 +3 Quadriceps weight* -54 -43 -24 -16 Tibialis anterior weight* -35 -29 -5 +5 Grip strength -12 +16 +15 +26 *Normalized by body weight. Conclusion SPI-62 prevented several CORT adverse effects in mouse, demonstrating that blockade of local intracellular glucocorticoid activation by a HSD-1 inhibitor in target tissues can mitigate glucocorticoid toxicity. These results suggest that SPI-62 has potential to similarly mitigate adverse effects of glucocorticoid medications in human. A placebo-controlled Phase 2 clinical trial has been initiated to compare prednisolone effects with and without SPI-62. Up to 48 patients diagnosed with polymyalgia rheumatica, on stable prednisolone 10 mg daily for at least 2 weeks, and with stable disease inactivity based on acute phase biomarkers will continue prednisolone 10 mg daily for 4 weeks, during which they will receive SPI-62 or placebo for 2 weeks each. Acute phase and other immune function biomarkers, symptom measures, and biomarkers of prednisolone adverse effects will be assessed at baseline and after each 2-week period. After analysis of data from a first cohort of 12 patients the prednisolone dose might be adjusted, in blinded fashion, during the SPI-62 period to maintain equipotency on acute phase biomarker suppression. Disclosure of Interests Xingyu Pan: None declared, Qiongqiong Hou: None declared, Jiahui Xu: None declared, Yake Ma: None declared, Jiawen Li: None declared, Min Li: None declared, Jing Su: None declared, Xuerou Shi: None declared, William Bracken Consultant of: Sparrow Pharmaceuticals, David Katz Shareholder of: Sparrow Pharmaceuticals, Employee of: Sparrow Pharmaceuticals